c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice.

AIMS/HYPOTHESIS: High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance. METHODS: The expression of c-Abl in different fat tissues from obese humans or mice fed a high-fat diet (HFD) were first analysed by western blotting and quantitative PCR. We employed conditional deletion of the c-Abl gene (also known as Abl1) in adipose tissue using Fabp4-Cre and 6-week-old mice were fed with either a chow diet (CD) or an HFD. Age-matched wild-type mice were treated with the c-Abl inhibitor nilotinib or with vehicle and exposed to either CD or HFD, followed by analysis of body mass, fat mass, glucose and insulin tolerance. Histological staining, ELISA and biochemical analysis were used to clarify details of changes in physiology and molecular signalling. RESULTS: c-Abl was highly expressed in subcutaneous fat from obese humans and HFD-induced obese mice. Conditional knockout of c-Abl in adipose tissue improved insulin sensitivity and mitigated HFD-induced body mass gain, hyperglycaemia and hyperinsulinaemia. Consistently, treatment with nilotinib significantly reduced fat mass and improved insulin sensitivity in HFD-fed mice. Further biochemical analyses suggested that c-Abl inhibition improved whole-body insulin sensitivity by reducing HFD-triggered insulin resistance and increasing adiponectin in subcutaneous fat. CONCLUSIONS/INTERPRETATION: Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders.

GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein.

Dengue virus infects more than 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here, we show that the allosteric Abl kinase inhibitor GNF-2 interferes with dengue virus replication via activity mediated by cellular Abl kinases but additionally blocks viral entry via an Abl-independent mechanism. To characterize this newly discovered antiviral activity, we developed disubstituted pyrimidines that block dengue virus entry with structure-activity relationships distinct from those driving kinase inhibition. We demonstrate that biotin- and fluorophore-conjugated derivatives of GNF-2 interact with the dengue glycoprotein, E, in the pre-fusion conformation that exists on the virion surface, and that this interaction inhibits viral entry. This study establishes GNF-2 as an antiviral compound with polypharmacological activity and provides "lead" compounds for further optimization efforts.

Role of the hybrid Bcr/Abl kinase in the pathogenesis of chronic myeloid leukemia lacking C-Abl and CXCR4 proteins.

Philadelphia chromosome is a result of chromosomal rearrangement that leads to the appearing of the hybrid gene bcr/abl. A hybrid mRNA transcribes from bcr-promoter and many copies of hybrid molecules of Bcr/Abl protein are formed as a result of bcr/abl gene expression. It is supposed that a hybrid Abl molecule, replacing the normal one, in majority of cases functions abnormally or does not function at all. Also it is possible that Abl moiety of Bcr/Abl protein which is possibly recognized by some hypothetical cell control system interpreted by cell as an overproduction of c-abl. This, probably, leads to blocking the normal C-Abl molecules production from the normal c-abl gene transcribed from the second non-aberrant chromosome 9. Based on C-Abl physiological functions in conjunction with the most important proteins of which functions directly depend on its activity we tried to outline the research directions that might explain disruptions of the processes at chronic myeloleukosis such as cell migration due to CXCL12/CXCR4 axis activation, reparation, apoptosis, control for mitochondria state, and to propose new perspective therapeutic approaches based on all this knowledge.

The association of cortactin with profilin-1 is critical for smooth muscle contraction.

Profilin-1 (Pfn-1) is an actin-regulatory protein that has a role in modulating smooth muscle contraction. However, the mechanisms that regulate Pfn-1 in smooth muscle are not fully understood. Here, stimulation with acetylcholine induced an increase in the association of the adapter protein cortactin with Pfn-1 in smooth muscle cells/tissues. Furthermore, disruption of the protein/protein interaction by a cell-permeable peptide (CTTN-I peptide) attenuated actin polymerization and smooth muscle contraction without affecting myosin light chain phosphorylation at Ser-19. Knockdown of cortactin by lentivirus-mediated RNAi also diminished actin polymerization and smooth muscle force development. However, cortactin knockdown did not affect myosin activation. In addition, cortactin phosphorylation has been implicated in nonmuscle cell migration. In this study, acetylcholine stimulation induced cortactin phosphorylation at Tyr-421 in smooth muscle cells. Phenylalanine substitution at this position impaired cortactin/Pfn-1 interaction in response to contractile activation. c-Abl is a tyrosine kinase that is necessary for actin dynamics and contraction in smooth muscle. Here, c-Abl silencing inhibited the agonist-induced cortactin phosphorylation and the association of cortactin with Pfn-1. Finally, treatment with CTTN-I peptide reduced airway resistance and smooth muscle hyperreactivity in a murine model of asthma. These results suggest that the interaction of cortactin with Pfn-1 plays a pivotal role in regulating actin dynamics, smooth muscle contraction, and airway hyperresponsiveness in asthma. The association of cortactin with Pfn-1 is regulated by c-Abl-mediated cortactin phosphorylation.

The capable ABL: what is its biological function?

The mammalian ABL1 gene encodes the ubiquitously expressed nonreceptor tyrosine kinase ABL. In response to growth factors, cytokines, cell adhesion, DNA damage, oxidative stress, and other signals, ABL is activated to stimulate cell proliferation or differentiation, survival or death, retraction, or migration. ABL also regulates specialized functions such as antigen receptor signaling in lymphocytes, synapse formation in neurons, and bacterial adhesion to intestinal epithelial cells. Although discovered as the proto-oncogene from which the Abelson leukemia virus derived its Gag-v-Abl oncogene, recent results have linked ABL kinase activation to neuronal degeneration. This body of knowledge on ABL seems confusing because it does not fit the one-gene-one-function paradigm. Without question, ABL capabilities are encoded by its gene sequence and that molecular blueprint designs this kinase to be regulated by subcellular location-dependent interactions with inhibitors and substrate activators. Furthermore, ABL shuttles between the nucleus and the cytoplasm where it binds DNA and actin--two biopolymers with fundamental roles in almost all biological processes. Taken together, the cumulated results from analyses of ABL structure-function, ABL mutant mouse phenotypes, and ABL substrates suggest that this tyrosine kinase does not have its own agenda but that, instead, it has evolved to serve a variety of tissue-specific and context-dependent biological functions.

Role of Abl in airway hyperresponsiveness and airway remodeling.

BACKGROUND: Asthma is a chronic disease that is characterized by airway hyperresponsiveness and airway remodeling. The underlying mechanisms that mediate the pathological processes are not fully understood. Abl is a non-receptor protein tyrosine kinase that has a role in the regulation of smooth muscle contraction and smooth muscle cell proliferation in vitro. The role of Abl in airway hyperresponsiveness and airway remodeling in vivo is largely unknown. METHODS: To evaluate the role of Abl in asthma pathology, we assessed the expression of Abl in airway tissues from the ovalbumin sensitized and challenged mouse model, and human asthmatic airway smooth muscle cells. In addition, we generated conditional knockout mice in which Abl expression in smooth muscle was disrupted, and then evaluated the effects of Abl conditional knockout on airway resistance, smooth muscle mass, cell proliferation, IL-13 and CCL2 in the mouse model of asthma. Furthermore, we determined the effects of the Abl pharmacological inhibitors imatinib and GNF-5 on these processes in the animal model of asthma. RESULTS: The expression of Abl was upregulated in airway tissues of the animal model of asthma and in airway smooth muscle cells of patients with severe asthma. Conditional knockout of Abl attenuated airway resistance, smooth muscle mass and staining of proliferating cell nuclear antigen in the airway of mice sensitized and challenged with ovalbumin. Interestingly, conditional knockout of Abl did not affect the levels of IL-13 and CCL2 in bronchoalveolar lavage fluid of animals treated with ovalbumin. However, treatment with imatinib and GNF-5 inhibited the ovalbumin-induced increase in IL-13 and CCL2 as well as airway resistance and smooth muscle growth in animals. CONCLUSIONS: These results suggest that the altered expression of Abl in airway smooth muscle may play a critical role in the development of airway hyperresponsiveness and airway remodeling in asthma. Our findings support the concept that Abl may be a novel target for the development of new therapy to treat asthma.

Formation of long and winding nuclear F-actin bundles by nuclear c-Abl tyrosine kinase.

The non-receptor-type tyrosine kinase c-Abl is involved in actin dynamics in the cytoplasm. Having three nuclear localization signals (NLSs) and one nuclear export signal, c-Abl shuttles between the nucleus and the cytoplasm. Although monomeric actin and filamentous actin (F-actin) are present in the nucleus, little is known about the relationship between c-Abl and nuclear actin dynamics. Here, we show that nuclear-localized c-Abl induces nuclear F-actin formation. Adriamycin-induced DNA damage together with leptomycin B treatment accumulates c-Abl into the nucleus and increases the levels of nuclear F-actin. Treatment of c-Abl-knockdown cells with Adriamycin and leptomycin B barely increases the nuclear F-actin levels. Expression of nuclear-targeted c-Abl (NLS-c-Abl) increases the levels of nuclear F-actin even without Adriamycin, and the increased levels of nuclear F-actin are not inhibited by inactivation of Abl kinase activity. Intriguingly, expression of NLS-c-Abl induces the formation of long and winding bundles of F-actin within the nucleus in a c-Abl kinase activity-dependent manner. Furthermore, NLS-c-AblΔC, which lacks the actin-binding domain but has the full tyrosine kinase activity, is incapable of forming nuclear F-actin and in particular long and winding nuclear F-actin bundles. These results suggest that nuclear c-Abl plays critical roles in actin dynamics within the nucleus.

Genetic disruption of Abl nuclear import reduces renal apoptosis in a mouse model of cisplatin-induced nephrotoxicity.

DNA damage activates nuclear Abl tyrosine kinase to stimulate intrinsic apoptosis in cancer cell lines and mouse embryonic stem cells. To examine the in vivo function of nuclear Abl in apoptosis, we generated Abl-µNLS (µ, mutated in nuclear localization signals) mice. We show here that cisplatin-induced apoptosis is defective in the renal proximal tubule cells (RPTC) from the Abl(µ/µ) mice. When injected with cisplatin, we found similar levels of platinum in the Abl(+/+) and the Abl(µ/µ) kidneys, as well as similar initial inductions of p53 and PUMAα expression. However, the accumulation of p53 and PUMAα could not be sustained in the Abl(µ/µ) kidneys, leading to reductions in renal apoptosis and tubule damage. Co-treatment of cisplatin with the Abl kinase inhibitor, imatinib, reduced the accumulation of p53 and PUMAα in the Abl(+/+) but not in the Abl(µ/µ) kidneys. The residual apoptosis in the Abl(µ/µ) mice was not further reduced in the Abl(µ/µ); p53(-/-) double-mutant mice, suggesting that nuclear Abl and p53 are epistatic to each other in this apoptosis response. Although apoptosis and tubule damage were reduced, cisplatin-induced increases in phospho-Stat-1 and blood urea nitrogen were similar between the Abl(+/+) and the Abl(µ/µ) kidneys, indicating that RPTC apoptosis is not the only factor in cisplatin-induced nephrotoxicity. These results provide in vivo evidence for the pro-apoptotic function of Abl, and show that its nuclear localization and tyrosine kinase activity are both required for the sustained expression of p53 and PUMAα in cisplatin-induced renal apoptosis.

Imatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro.

OBJECTIVES: Systemic sclerosis (SSc) is a heterogeneous multifactorial disease dominated by progressive skin and internal organ fibrosis that is driven in part by transforming growth factor-beta (TGF-ß). An important downstream target of TGF-ß is the Abelson (c-Abl) tyrosine kinase, and its inhibition by imatinib mesylate (Gleevec) attenuates fibrosis in mice. Here we examined the effect of c-Abl activation and blockade in explanted healthy control and SSc fibroblasts. METHODS: Skin biopsies and explanted fibroblasts from healthy subjects and patients with SSc were studied. Changes in genome-wide expression patterns in imatinib-treated control and SSc fibroblasts were analysed by DNA microarray. RESULTS: Treatment of control fibroblasts with TGF-ß resulted in activation of c-Abl and stimulation of fibrotic gene expression that was prevented by imatinib. Moreover, imatinib reduced basal collagen gene expression in SSc but not control fibroblasts. No significant differences in tissue levels of c-Abl and phospho-c-Abl were detected between SSc and control skin biopsies. In vitro, imatinib induced dramatic changes in the expression of genes involved in fibrosis, cardiovascular disease, inflammation, and lipid and cholesterol metabolism. Remarkably, of the 587-imatinib-responsive genes, 91% showed significant change in SSc fibroblasts, but only 12% in control fibroblasts. CONCLUSIONS: c-Abl plays a key role in fibrotic responses. Imatinib treatment results in dramatic changes in gene expression in SSc fibroblasts but has only modest effects in control fibroblasts. These data provide novel insights into the mechanisms underlying the antifibrotic effect of imatinib in SSc.

c-Abl phosphorylation of Mdm2 facilitates Mdm2-Mdmx complex formation.

Mdm2 and Mdmx are oncoproteins that have essential yet nonredundant roles in development and function as part of a multicomponent ubiquitinating complex that targets p53 for proteasomal degradation. However, in response to DNA damage, Mdm2 and Mdmx are phosphorylated and protect p53 through various mechanisms. It has been predicted that Mdm2-Mdmx complex formation modulates Mdm2 ligase activity, yet the mechanism that promotes formation of Mdm2-Mdmx complexes is unknown. Here, we show that optimal Mdm2-Mdmx complex formation requires c-Abl phosphorylation of Mdm2 both in vitro and in vivo. In addition, Abl phosphorylation of Mdm2 is required for efficient ubiquitination of Mdmx in vitro, and eliminating c-Abl signaling, using c-Abl(-/-) knock-out murine embryonic fibroblasts, led to a decrease in Mdmx ubiquitination. Further, p53 levels are not induced as efficiently in c-Abl(-/-) murine embryonic fibroblasts following DNA damage. Overall, these results define a direct link between genotoxic stress-activated c-Abl kinase signaling and Mdm2-Mdmx complex formation. Our results add an important regulatory mechanism for the activation of p53 in response to DNA damage.

NF-kappaB activity is constitutively elevated in c-Abl null fibroblasts.

The c-abl proto-oncogene encodes a nonreceptor tyrosine kinase involved in many cellular processes, including signaling from growth factor and antigen receptors, remodeling the cytoskeleton, and responding to DNA damage and oxidative stress. Many downstream pathways are affected by c-Abl. Elevated c-Abl kinase activity can inhibit NF-kappaB activity by stabilizing the inhibitory protein IkappaB alpha, raising the possibility that c-Abl-deficient cells might have increased NF-kappaB activity. We examined the levels of NF-kappaB activity in primary mouse embryonic fibroblasts (MEFs) derived from wild-type and c-Abl knockout mice and found that the knockout MEFs indeed exhibited elevated NF-kappaB activity in response to stimulation as well as constitutively elevated NF-kappaB activity. Thus, endogenous c-Abl is a negative regulator of basal and inducible NF-kappaB activity. Examination of various points of NF-kappaB regulation revealed that unstimulated c-Abl knockout MEFs do not exhibit an increase in IkappaB alpha degradation, p65/RelA nuclear translocation, or DNA binding of NF-kappaB subunits. They do, however, show reduced levels of the histone deacetylase HDAC1, a negative regulator of basal NF-kappaB activity. Unstimulated c-Abl knockout MEFs are less responsive to induction of NF-kappaB activity by trichostatin A, an HDAC inhibitor, suggesting that c-Abl might play a role in the HDAC-mediated repression of basal NF-kappaB activity.

Endogenous cAbl regulates receptor endocytosis.

There are two key processes underlying ligand-induced receptor endocytosis: receptor ubiquitylation and remodeling of the actin cytoskeleton. Tyrosine kinases play critical roles in both receptor endocytosis and actin reorganization. Interestingly, members of the Abl family are the only known tyrosine kinases that possess an actin-binding domain and thus have the potential to directly regulate the actin cytoskeleton. However, the role of non-transforming cAbl in receptor endocytosis remains undefined. We report that cAbl promotes ligand-induced antigen receptor endocytosis in B lymphocytes. We show that pharmacologic inhibition or genetic deletion of cAbl causes a defect in tyrosine phosphorylation of the cytoskeletal adapter CrkII. cAbl inhibition or ablation also impairs Rac activation downstream of CrkII, as well as antigen receptor capping and endocytosis. Although phosphorylation of CrkII has been suggested to maintain it in a closed inactive conformation, we demonstrate that it is in fact essential for the activation of Rac. On the other hand, association of CrkII with cCbl, a key mediator of receptor ubiquitylation, does not require CrkII phosphorylation and is cAbl-independent. Phosphorylation of cCbl itself is also cAbl-independent. Our results thus indicate that CrkII links receptor engagement to cytoskeletal remodeling by coupling cCbl- and cAbl-mediated signaling pathways that cooperatively regulate ligand-induced receptor endocytosis.

T cell survival and function requires the c-Abl tyrosine kinase.

C-Abl (Abl) regulates multiple cellular processes, including proliferation, survival, shape determination and motility, and participates in cellular responses to genotoxic and oxidative stress stimuli. Mice lacking Abl exhibit retarded growth, osteoporosis and defects in the immune system resulting in lymphopoenia and susceptibility to infections, leading to early death. To define the role of Abl in the regulation of adult T cells we ablated Abl exclusively in T cells by generating mice with floxed abl alleles and expressing an Lck-Cre transgene (Abl-T(-/-)). These mice exhibited thymic atrophy and abnormally reduced T cell numbers in the periphery. The thymic atrophy was caused by increased susceptibility of thymocytes to cell death. Importantly, Abl deficient T cells displayed abnormally reduced response to mitogenic stimulation in vitro. Consequently, Abl-T(-/-) mice exhibited impaired ability to reject syngeneic tumor, to induce T-mediated tumor cell killing, and to generate anti-tumor antibodies. These results demonstrate a cell-autonomous role for Abl in T cell function and survival.

The c-Abl tyrosine kinase regulates actin remodeling at the immune synapse.

Actin dynamics during T-cell activation are controlled by the coordinate action of multiple actin regulatory proteins, functioning downstream of a complex network of kinases and other signaling molecules. The c-Abl nonreceptor tyrosine kinase regulates actin responses in nonhematopoietic cells, but its function in T cells is poorly understood. Using kinase inhibitors, RNAi, and conditional knockout mice, we investigated the role of c-Abl in controlling the T-cell actin response. We find that c-Abl is required for normal actin polymerization and lamellipodial spreading at the immune synapse, and for downstream events leading to efficient interleukin-2 production. c-Abl also plays a key role in signaling chemokine-induced T-cell migration. c-Abl is required for the appropriate function of 2 proteins known to be important for controlling actin responses to T-cell receptor (TCR) engagement, the actin-stabilizing adapter protein HS1, and the Rac1-dependent actin polymerizing protein WAVE2. c-Abl binds to phospho-HS1 via its SH2 domains and is required for full tyrosine phosphorylation of HS1 during T-cell activation. In addition, c-Abl is required for normal localization of WAVE2 to the immune synapse (IS). These studies identify c-Abl as a key player in the signaling cascade, leading to actin reorganization during T-cell activation.

Defective T cell development and function in the absence of Abelson kinases.

Thymocyte proliferation, survival, and differentiation are tightly controlled by signaling from the pre-TCR. In this study, we show for the first time that the Abelson (Abl) kinases regulate proximal signaling downstream of the pre-TCR. Conditional deletion of Abl kinases in thymocytes reveals a cell-autonomous role for these proteins in T cell development. The conditional knockout mice have reduced numbers of thymocytes, exhibit an increase in the percentage of the CD4(-)CD8(-) double-negative population, and are partially blocked in the transition to the CD4(+)CD8(+) double-positive stage. Moreover, the total number of T cells is greatly reduced in the Abl mutant mice, and the null T cells exhibit impaired TCR-induced signaling, proliferation, and cytokine production. Notably, Abl mutant mice are compromised in their ability to produce IFN-positive CD8 T cells and exhibit impaired CD8(+) T cell expansion in vivo upon Listeria monocytogenes infection. Furthermore, Ab production in response to T cell-dependent Ag is severely impaired in the Abl mutant mice. Together these findings reveal cell-autonomous roles for the Abl family kinases in both T cell development and mature T cell function, and show that loss of these kinases specifically in T cells results in compromised immunity.

Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice.

Previous studies on c-Abl-deficient mice have shown high post-natal mortality and lymphopenia. However, the mechanisms by which c-Abl may influence B lymphopoiesis remain obscure. In this study, we analyzed B cell sub-populations at various differentiation stages in the bone marrow (BM) of c-Abl-deficient mice. Phenotypic analyses revealed that c-Abl(-/-) pro-B cells were reduced to half of normal incidence and absolute number, while pre-B cells showed an even greater reduction. Both c-Abl(-/-) pro-B and pre-B cell populations showed considerably elevated apoptosis ex vivo and in short-term culture but their cell cycle progression was not impaired. In contrast, apoptosis of immature IgM(+)IgD(-) B lymphocytes remained at normal control levels. Inhibition of c-Abl activity by STI571 in normal BM cultures significantly increased apoptosis in B cell precursors while the survival of immature B cells was not affected. To determine whether c-Abl deficiency affects Ig heavy-chain rearrangement, we found that the frequency of V(D)J recombination was markedly reduced by 15-fold in c-Abl(-/-) pro-B cells compared with the control values. However, no perturbation in the levels of signal-end recombination intermediates was found. Taken together, we propose that c-Abl mediates a stage-specific anti-apoptotic response in precursor B cells and is required for efficient V(D)J recombination during B cell development.

The tyrosine kinase c-Abl protects c-Jun from ubiquitination-mediated degradation in T cells.

The cross-talk of ubiquitination with other types of posttranscriptional modifications, such as phosphorylation, regulates the stability of many proteins. We have previously demonstrated that c-Jun is a substrate of Itch, a HECT-type E3 ubiquitin ligase. c-Jun is also a substrate of the tyrosine kinase c-Abl. Here we report that genetic ablation of c-Abl accelerated c-Jun degradation. Phosphorylation of the tyrosine within the PPXY motif by c-Abl inhibited c-Jun ubiquitination and its binding by Itch. The nuclear localization of c-Abl, triggered by T-cell activation signals, was essential for its activity in regulating c-Jun transcription activity. These findings define a potential molecular mechanism for the immunodeficiency in mice lacking the c-abl gene.

A kinase-independent function of c-Abl in promoting proteolytic destruction of damaged DNA binding proteins.

Damaged DNA binding proteins (DDBs) play a critical role in the initial recognition of UV-damaged DNA and mediate recruitment of nucleotide excision repair factors. Previous studies identified DDB2 as a target of the CUL-4A ubiquitin ligase. However, the biochemical mechanism governing DDB proteolysis and its underlying physiological function in the removal of UV-induced DNA damage are largely unknown. Here, we report that the c-Abl nonreceptor tyrosine kinase negatively regulates the repair of UV-induced photolesions on genomic DNA. Biochemical studies revealed that c-Abl promotes CUL-4A-mediated DDB ubiquitination and degradation in a manner that does not require its tyrosine kinase activity both under normal growth conditions and following UV irradiation. Moreover, c-Abl activates DDB degradation in part by alleviating the inhibitory effect of CAND1/TIP120A on CUL-4A. These results revealed a kinase-independent function of c-Abl in a ubiquitin-proteolytic pathway that regulates the damage recognition step of nucleotide excision repair.

c-Abl acetylation by histone acetyltransferases regulates its nuclear-cytoplasmic localization.

c-Abl function is strictly dependent on its subcellular localization. Using an in vitro approach, we identify c-Abl as a new substrate for p300, CBP (CREB-binding protein) and PCAF (p300/CBP-associated factor) histone acetyltransferases. Remarkably, acetylation markedly alters its subcellular localization. Point mutagenesis indicated that Lys 730, located in the second nuclear localization signal, is the main target of p300 activity. It has previously been reported that c-Abl accumulates in the cytoplasm during myogenic differentiation. Here, we show that c-Abl protein is acetylated at early stages of myogenic differentiation. Indeed, acetylation on Lys 730 drives c-Abl accumulation in the cytoplasm and promotes differentiation. Thus, Lys 730 acetylation is a novel post-translational modification of c-Abl and a novel mechanism for modulating its subcellular localization that contributes to myogenic differentiation.